Project Summary/Abstract This proposal describes the five-year career development plan for Principal Investigator Cole J. Ferguson, MD, PhD, with the goal of preparing him for an independent research career as an academic physician- scientist. Dr. Ferguson enrolled in the Physician-Scientist Training Program within the Pathology & Immunology Department at Washington University after completing the MD/PhD program at the University of Michigan. Following the Anatomic and Neuropathology residency-fellowship, Dr. Ferguson began working in the laboratory of Azad Bonni, where he studies the ubiquitin-proteasome system (UPS) in inherited neurodevelopmental disorders. The long-term goal of Dr. Ferguson's research is to improve the understanding of the molecular and cellular pathogenesis of this diverse class of disorders. For this proposal, he has genetically engineered a mutant mouse to study a novel inherited neurodevelopmental disorder caused by mutation in a major E3 ubiquitin ligase complex. While investigating brain development in mutant mice, he uncovered a major mechanism of epigenetic regulation during the transition from dividing progenitors to functional neurons. Aim 1 will characterize the molecular cascade that underlies aberrant chromatin maturation, while Aim 2 will explore the consequences on gene expression in the developing versus mature brain. In the course of this project, Dr. Ferguson will become an expert in imaging, biochemical and genomics approaches to study epigenetics in the brain. This project has the potential for significant expansion and is an outstanding scientific foundation for the start of Dr. Ferguson's independent laboratory. Washington University is the ideal setting for Dr. Ferguson to achieve these aims. His mentor Dr. Azad Bonni is Chair of the Neuroscience Department and a preeminent molecular neuroscientist who has pioneered the study of the UPS in brain development. Dr. Bonni has an outstanding record of training independent investigators in his laboratory. In addition, the Department of Neuroscience has expanded upon its tradition of collaboration and cutting-edge experimentation across both molecular and systems neuroscience. This proposal will make extensive use of the School of Medicine's world-class core facilities in microscopy and next- generation sequencing. The expertise of Dr. Ferguson's esteemed scientific advisory panel encompasses all aspects of this proposal, including neurodevelopmental disorders, epigenetic regulation, and ubiquitin signaling in brain development. The Pathology Physician-Scientist Training Program committee will play an active role in Dr. Ferguson's career development, and this program has an outstanding record of transitioning trainees into independent investigators through the K08 mechanism. In short, this proposal will make progress on several important aspects of epigenetic regulation in developmental neurobiology, while providing invaluable technical training and career development to a highly promising physician-scientist.